Processes in the brain and other organs involving serotonin as a neurotransmitter have been a major field of pharmacological research for some decades. A large number of processes which depend on serotonin have been identified, and numerous therapeutic compounds which affect such processes are in widespread use. More than a dozen receptors which are acted upon by serotonin have been identified. Some of the receptors' physiological mechanisms have been identified, and others are still the subject of extended and active research. One of the more recently identified serotonin receptors is known as 5-HT.sub.4. Bockaert J., Fozard J., Dumuis A., et al., "The 5-HT.sub.4 Receptor: A Place in the Sun", Trends Pharmacol. Sci., 13, 141, 1992. Therapeutic methods making use of the 5-HT.sub.4 receptor have been held back by the lack of compounds which affect the 5-HT.sub.4 receptor without substantial effect at other receptors.
Recently, a series of new pharmaceutical agents which have high affinity and selectivity at the 5-HT.sub.4 receptor have been identified and disclosed in U.S. Pat. No. 5,654,320, the entirety of which is herein incorporated by reference. A key intermediate to those compounds, and compounds disclosed within which also have high affinity and selectivity at the 5-HT.sub.4 receptor, is the indazolic ester of formula I: ##STR2##
Compared to the many synthetic routes leading to compounds of formula I (See e.g. Heterocyclic Compounds, Vol. 5, R. C. Elderfield, Ed., John Wiley & Sons, New York, 1957, pp. 162-193), dehydrogenation of compounds of formula II: ##STR3## is most direct. However, the following considerations limit the practical utility of this synthesis: extreme reaction conditions are required for dehydrogenation (palladium on carbon in decalin at 200.degree. C. for 48 hours), and overall yields are low (58% when R and R.sup.1 are both hydrogen, and the C.sub.1 -C.sub.4 alkyl group is ethyl). F. Piozzi, A. Umani-Ronchi, L. Merlini, Gazz.Chim.Ital. 95, 814 (1965), and J. P. Burnett, C. Ainsworth, J. Org. Chem. 23, 1382, (1958).
A more recent synthesis published in 1984 provided access to the indazole ring system by the route shown below where R.sup.2 is hydrogen or phenyl: ##STR4## The above sequence represents a reduction of a ketone of formula III, a dehydration of the resulting compound IV, followed by an in situ aromatization of intermediate V. This two step synthesis is performed at 100.degree. C. in a dioxane solution of p-toluenesulfonic acid in the presence of palladium on carbon providing product at yields up to 73%. La Rosa, C., Dalla Croce, P., Synthesis, 982, (1984). The lower reaction temperatures can be attributed to the intermediate of formula V which is unstable toward oxidation.
This newer synthesis suffers in three respects. First, substitution at the 4 position of the indazole system is limited to hydrogen. Secondly, the necessity of performing the dehydration reaction in the presence of an acid at elevated temperatures could be incompatible with certain functional groups e.g. a hydroxyl group. Lastly, yields for the reaction have much room for improvement. An improvement over the prior art would be a process that does not require extreme temperatures or acid, is higher yielding, and is not dependent upon a 4-keto intermediate.